A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

Coll, Rebecca C., Robertson, Avril A. B., Chae, Jae Jin, Higgins, Sarah C., Muñoz-Planillo, Raúl, Inserra, Marco C., Vetter, Irina, Dungan, Lara S., Monks, Brian G., Stütz, Andrea, Croker, Daniel E., Butler, Mark S., Haneklaus, Moritz, Sutton, Caroline E., Núñez, Gabriel, Latz, Eicke, Kästner, Daniel L., Mills, Kingston H. G., Masters, Seth L., Schroder, Kate, Cooper, Matthew A. and O'Neill, Luke A. J. (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine, 21 3: 248-257. doi:10.1038/nm.3806

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Author Coll, Rebecca C.
Robertson, Avril A. B.
Chae, Jae Jin
Higgins, Sarah C.
Muñoz-Planillo, Raúl
Inserra, Marco C.
Vetter, Irina
Dungan, Lara S.
Monks, Brian G.
Stütz, Andrea
Croker, Daniel E.
Butler, Mark S.
Haneklaus, Moritz
Sutton, Caroline E.
Núñez, Gabriel
Latz, Eicke
Kästner, Daniel L.
Mills, Kingston H. G.
Masters, Seth L.
Schroder, Kate
Cooper, Matthew A.
O'Neill, Luke A. J.
Title A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
Journal name Nature Medicine   Check publisher's open access policy
ISSN 1078-8956
Publication date 2015-03
Year available 2015
Sub-type Article (original research)
DOI 10.1038/nm.3806
Volume 21
Issue 3
Start page 248
End page 257
Total pages 10
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Collection year 2016
Language eng
Formatted abstract
The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle–Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.
Keyword Inflammatory diseases
NLRP3 inflammasome
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Pharmacy Publications
Institute for Molecular Bioscience - Publications
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Created: Mon, 23 Feb 2015, 14:17:41 EST by Dr Kate Schroder on behalf of Institute for Molecular Bioscience